Project Summary ? Project #1 A recent and important advance in bone biology has been the demonstration that bone is an endocrine organ secreting at least two hormones, FGF23 and osteocalcin. Osteocalcin, the bone-derived hormone we are most familiar with, is an osteoblast-derived molecule that favors insulin secretion and glucose homeostasis, testosterone production and male fertility in mice and humans. A systematic analysis of osteocalcin function revealed that this hormone crosses the blood brain barrier, binds to serotonergic neurons in the raphe nuclei and catecholaminergic neurons in the midbrain, favors serotonin, dopamine, catectrolamine synthesis, inhibits the one of GABA and enhances adult neurogenesis. At least some of these functions occur through CREB. As a result of the disruption of these functions, Osteocalcin-/- mice display increased anxiety and depression and loss of spatial learning and memory while osteocalcin injections in WT mice decrease their anxiety. In a further development we also showed that during embryonic development maternally derived osteocalcin crosses the placenta, prevents neuronal apoptosis in the hippocampus and is needed for optimal spatial learning and memory in the adult offspring. These results reveal important functions of osteocalcin as a regulator of brain development and cognitive functions. As such it is one of the long sought-after molecules modulating the central control of bone mass and a mediator of the maternal influence on neurological and psychiatric health of the offspring. Based on these and on other preliminary data we now propose the following specific aims: ? To determine whether peripheral delivery of Ocn is sufficient to improve cognitive functions in WT mice as they age. ? To evaluate genetically the impact of the mother's Ocn on metabolic and cognition status of the adult offspring at several time points during their livelihood. ? To evaluate whether modifying bone formation in the offspring or the mother impinges on metabolic status and cognition in adult and aging offspring. ? To determine whether alteration in bone resorption impinges on cognition in aging mice.